ABSTRACT This proposal is to request support for a Keystone Symposia meeting entitled Tolerance and Autoimmunity, organized by Betty Diamond and Diane J. Mathis, which will be held in Taos, New Mexico from February 21 ? 26, 2010. Elegant studies of central T and B cell tolerance have led to the identification of multiple mechanisms that remove or silence autoreactive cells during their maturation. However, these studies also remind us that some autoreactive cells do mature to immunocompetence in all individuals. Furthermore, studies of the B cell response to antigen have clearly demonstrated that autoreactivity can arise de novo in antigen-activated cells, which also requires silencing. Finally, it has now been established in studies of multiple autoimmune diseases that a critical checkpoint exists between autoreactivity and tissue injury, one of the issues about which we remain most ignorant. Understanding peripheral mechanisms for maintaining selftolerance offers promise for better therapies for autoimmune disease. The proper implementation of this new knowledge requires an understanding of similarities and differences between animal models and human disease. This meeting will bring together basic, translational and clinical investigators to explore these new observations and use them to develop new perspectives on autoimmune diseases and new approaches to therapies for these diseases.